This proposal describes a 5 year training program for the development of an academic career in cardiac developmental biology and Neonatology. The candidate is in his final year of the Pediatric Scientist Development Program and Neonatology fellowship at the Children's Hospital of Philadelphia (CHOP). The program will expand a body of work in the developmental biology of newborn cardiac diseases. Jonathan Epstein, MD, a recognized leader in the fields of cardiovascular development and transcriptional regulation, will supervise the training program. He is a Professor of Medicine and Director of the Penn Molecular Cardiology Research Center (MCRC). He has mentored numerous postdoctoral fellows and graduate students. An advisory committee of distinguished scientists with expertise in academic Pediatrics and developmental biology will provide scientific and career advice. The environment of CHOP and the MCRC will provide extensive resources, collaborations, core facilities and intellectual expertise. This is an ideal training setting to develop a skill set in order to transition to an independent career as a physician-scientist. Participation in didactic courses and faculty professional development seminars will enhance the educational success of the program. DiGeorge syndrome (DCS) is a common syndrome and is frequently associated with deletions on chromosome 22q11. Many patients with conotruncal heart defects carry a 22q11 deletion. Mouse models have implicated Tbx1, encoding a nuclear transcription factor, as a critical gene within the commonly deleted region. Some patients with typical DGS features, but without the 22q11 deletion, have mutations in TBX1. The mechanisms by which these mutations cause disease are unclear. The central hypothesis of this proposal is that TBX1 mutations cause DGS by affecting the ability of its nuclear complex to modulate transcriptional targets. Tbx1 direct targets and its transcriptional complex are largely unknown. We have identified a potential transcriptional cofactor, Ash2l. The specific aims are to 1) Determine the DNA binding site that confers optimal Tbx1 dependent activation, and 2) To characterize the function of Ash2l and its interaction with Tbxl Relevance to Public Health: The results of this work will be directly relevant toward understanding mechanisms of human embryonic development. In the future, these findings may help children born with common and uncommon syndromes and those born with severe heart defects. (End of Abstract)